There is an association between severe hypoglycemia and all-cause mortality, and patients who experience severe hypoglycemia are at greater risk of death in the short term after a hypoglycemic episode, a recent study found. The secondary analysis of the DEVOTE trial included 7,637 patients with type 2 diabetes (T2D) who were randomized to receive either insulin degludec or insulin glargine (100 units/ml) once daily in an even-driven, double-blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; CV death, nonfatal myocardial infarction, or nonfatal stroke). Researchers found:

There was a nonsignificant difference in the risk of MACE for patients who had experienced severe hypoglycemia during the trial vs individuals who had not (HR, 1.38).

There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycemia during the trial (HR, 2.51).

There was a higher risk of all-cause mortality 15, 30, 60, 90, 180, and 365 days after experiencing severe hypoglycemia compared with not experiencing severe hypoglycemia in the same time interval.

In the DEVOTE trial, which compared cardiovascular safety of insulin degludec vs insulin glargine in patients with type 2 diabetes at high risk of cardiovascular events, insulin degludec was noninferior to insulin glargine with regard to the primary outcome of the trial—cardiovascular events and mortality.1 In secondary analysis, there was a 40% lower rate of severe hypoglycemia and a 53% lower rate of nocturnal severe hypoglycemia with insulin degludec compared to glargine. In the current analysis, DEVOTE 3, results indicated that for those individuals who experienced severe hypoglycemia, whether in the insulin degludec or insulin glargine arm, there was over a 2-fold increase in mortality in the subsequent 15–365 days. In addition, in the DEVOTE 2 analysis, published in this same issue of Diabetologia, day-to-day fasting glucose variability was related to severe hypoglycemia, with less variability in the degludec arm.2 Interpreting this data is challenging, as the analysis of outcomes with hypoglycemia was essentially an observational trial within a randomized trial design,and thus, it contains all the usual limitations of any observational trial. Hypoglycemia may be a marker for those at higher risk of mortality, in essence a confounding variable, and hypoglycemia may or may not be causally related to the outcome of mortality. Nonetheless, there is no question that we should try to avoid severe hypoglycemia as one of the primary goals of treatment. —Neil Skolnik, MD